Retinoic acid regulates Schwann cell migration via NEDD9 induction by transcriptional and post-translational mechanisms.

Schwann cell migration is essential during the regenerative response to nerve injury, however, the factors that regulate this phenomenon are not yet clear. Here we describe that retinoic acid (RA), whose production and signaling activity are greatly enhanced during nerve regeneration, increases Schwann cell migration. This is accompanied by the up-regulation of NEDD9, a member of the CAS family of scaffold proteins previously implicated in migratory and invasive behavior in gliomas, melanomas and the neural crest cells from which Schwann cells derive. This RA-induced NEDD9 accumulation is due to augmented mRNA levels, as well as an increase of NEDD9 protein stability. Although all NEDD9 phospho-isoforms present in Schwann cells are induced by the retinoid, the hormone also changes its phosphorylation status, thus altering the ratio between the different isoforms. Silencing NEDD9 in Schwann cells had no effect on basal migratory ability, but completely abrogated RA-induced enhanced migration. Collectively, our results indicate that RA could be a major regulator of Schwann cell migration after nerve injury, thus offering a new insight into peripheral nerve repair.

Correcting non cephalic presentation with moxibustion: study protocol for a multi-centre randomised controlled trial in general practice.

BACKGROUND: Non cephalic presentation in childbirth involves various risks to both the mother and the foetus. The incidence in Spain is 3.8% of all full-term pregnancies. The most common technique used to end the gestation in cases of non cephalic presentation is that of caesarian section, and although it provokes a lower rate of morbi-mortality than does vaginal delivery in such situations, there remains the possibility of traumatic injury to the foetal head and neck, while maternal morbidity is also increased. The application of heat (moxibustion) to an acupuncture point, in order to correct non cephalic presentation, has been practised in China since ancient times, but as yet there is insufficient evidence of its real effectiveness. METHODS/DESIGN: The experimental design consists of a multi-centre randomised controlled trial with three parallel arms, used to compare real moxibustion, sham moxibustion and the natural course of events, among pregnant women with a non cephalic presentation and a gestational duration of 33-35 weeks (estimated by echography). The participants in the trial will be blinded to both interventions. The results obtained will be analyzed by professionals, blinded with respect to the allocation to the different types of intervention. In addition, we intend to carry out a economic analysis. DISCUSSION: This trial will contribute to the development of evidence concerning moxibustion in the correction of non cephalic presentations. The primary outcome variable is the proportion of cephalic presentations at term. As secondary outcomes, we will evaluate the proportion of cephalic presentations at week 38 of gestation, determined by echography, together with the safety of the technique, the specificity of moxibustion and the control of the blinding process. This study has been funded by the Health Ministry of the Andalusian Regional Government. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10634508.

Characterization of vitamin D receptor ligands with cell-specific and dissociated activity.

Although the main role of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is to regulate calcium homeostasis, the valuable therapeutic applications of this compound have led to the search of new 1,25-(OH)(2)D(3)-vitamin D receptor (VDR) ligands with less side effects. In this work we have characterized seven 1,25-(OH)(2)D(3) derivatives (ZK136607, ZK161422, ZK157202, ZK159222, ZK168492, ZK191732, and ZK168289). ZK157202 is an agonist that gives a pattern similar to that of 1,25-(OH)(2)D(3) or ZK161422 in limited trypsin digestion assays, is able to recruit p160 and VDR-interacting protein 205 coactivators, is as potent as 1,25-(OH)(2)D(3) to stimulate vitamin D response element-dependent transcription in HeLa cells, and acts as a superagonist in human embryonic kidney 293T cells. This compound is also more potent than the natural ligand to transrepress the activation of the retinoic acid receptor beta2 promoter by retinoic acid and the response of the collagenase promoter to 4alpha-12-O-tetradecanoylphorbol 13-acetate. ZK136607, ZK168492, ZK191732, and ZK168289 have a profile similar to that of the partial antagonist ZK159222. They induce an antagonistic-type proteolytic pattern, do not recruit classical coactivators, and have little transactivation potency. However, they act in a cell context-dependent manner because they lack activity in HeLa cells while presenting some agonistic activity in human embryonic kidney 293T cells, or vice versa. Furthermore, some of these compounds have a dissociated activity: they cannot transactivate but they are as potent as 1,25-(OH)(2)D(3) in transrepression assays. Together our results demonstrate the existence of novel VDR ligands with variable biological functions and dissociated activity. They should represent useful tools for studying VDR function and could have therapeutic utility.